Folic acid and pyridoxine are essential vitamins for man. Both play vital roles in cell replication, maturation, and production of intracellular proteins and heme pigments. A number of disease states, drugs and toxins have been associated with abnormalities in folic acid and pyridoxine metabolism with resultant prominent defects in hematopoiesis and hepatic cell function. The objective of the proposed research is, therefore, to gain a better understanding of the biochemical, physiological mechanisms involved in the metabolism of these vitamins. In the folate area, major attention will be given to studies of the pathways and kinetics of vitamin transport, tissue uptake and storage, congener formation, including the development of folate polyglutamates, tissue store release, biliary excretion and enterohepatic recirculation and, finally, target organ uptake utilization and breakdown. Intracellular pyridoxine metabolism will be studied to characterize the conversion of the vitamin to its biologically active phosphorylated forms and their subsequent transport into mitochondria. Specific studies will also be carried out to improve our knowledge and understanding of the relationship of disruptions in normal folic acid and pyridoxine kinetics and specific disease states such as the refractory sideroblastic anemia. Points of interruption of the normal metabolic pathways will be searched for to assist in the planning of specific therapeutic interventions.